Cyclic and heterocyclic N-substituted alpha-iminohydroxamic and -carboxylic acids

ABSTRACT

Cyclic and heterocyclic N-substituted α-iminohydroxamic and -carboxylic acids  
     Compounds of the formula I  
                 
 
     are suitable for preparing pharmaceuticals for the treatment of disorders in the course of which is involved an increased activity of matrix-degrading metalloproteinases.

[0001] Cyclic and heterocyclic N-substituted α-iminohydroxamic and-carboxylic acids

[0002] The invention relates to cyclic and heterocyclic N-substitutedα-imino-hydroxamic and -carboxylic acids, to processes for theirpreparation and to their use as pharmaceuticals.

[0003] EP 0 606 046 discloses some arylsulfonamidohydroxamic acidderivatives and their action as matrix metalloproteinase inhibitors.

[0004] In the effort to find further efficacious compounds for thetreatment of connective tissue disorders, it has now been found that theimino-hydroxamic acid derivatives according to the invention areinhibitors of metalloproteinases.

[0005] The invention relates to a compound of the formula I

[0006] and/or an optionally stereoisomeric form of the compound of theformula I and/or a physiologically tolerable salt of the compound of theformula I, where in the case i)

[0007] R¹ is

[0008] a) a radical of the formula II

[0009] b) a radical of the formula III

[0010] c) a radical of the formula IV

[0011] where Z is a radical of a heterocycle or a substitutedheterocycle such as

[0012] 1) pyrrole,

[0013] 2) thiazole,

[0014] 3) pyrazole,

[0015] 4) pyridine,

[0016] 5) imidazole,

[0017] 6) pyrrolidine,

[0018] 7) piperidine,

[0019] 8) thiophene,

[0020] 9) oxazole,

[0021] 10) isoxazole,

[0022] 11) morpholine or

[0023] 12) piperazine,

[0024] d) naphthyl,

[0025] e) naphthyl, mono- or trisubstituted by R², or

[0026] f) a radical of the formula V

[0027] where o is the number 1 or 2 and one of the carbon atoms in thering may be replaced by —O— or —S—, and

[0028] Q as part of the structural formula I

[0029] 1) is the structural moiety VI

[0030] 2) the structural moiety VII

[0031] 3) is the structural moiety VIII

[0032] 4) the structural moiety IX

[0033] 5) is the structural moiety X

[0034] where D is NR⁴ or S,

[0035] R² is

[0036] 1) phenyl or

[0037] 2) phenyl which is mono- to trisubstituted by

[0038] 2.1 hydroxyl,

[0039] 2.2 —O—R¹⁰, where R¹⁰

[0040] 1) is (C₁-C₆)-alkyl,

[0041] 2) is (C₃-C₆)-cycloalkyl,

[0042] 3) is benzyl or

[0043] 4) is phenyl,

[0044] 2.3 —COOH,

[0045] 2.4 (C₁-C₆)-alkyl,

[0046] 2.5 (C₃-C₆)-cycloalkyl-O—(C₁-C₄)-alkyl,

[0047] 2.6 halogen,

[0048] 2.7 —CN,

[0049] 2.8 —NO₂,

[0050] 2.9 —CF₃,

[0051] 2.10 —O—C(O)—R¹⁰ and R¹⁰ is as defined above,

[0052] 2.11 —O—C(O)-phenyl, mono- or disubstituted by R³,

[0053] 2.12 —C(O)—O—R¹⁰ and R¹⁰ is as defined above,

[0054] 2.13 methylenedioxo,

[0055] 2.14 —C(O)—NR¹¹R¹², where R¹¹ and R¹² may be identical ordifferent and each is

[0056] 1) a hydrogen atom,

[0057] 2) (C₁-C₄)-alkyl or

[0058] 3) benzyl or

[0059] 4) R¹¹ and R¹² together with the linking nitrogen atom form apyrrolidine, piperidine, morpholine or piperazine radical, or

[0060] 2.15 —NR¹³R¹⁴, where R¹³ is a hydrogen atom or (C₁-C₄)-alkyl and

[0061] R¹⁴

[0062] 1) is a hydrogen atom,

[0063] 2) is (C₁-C₄)-alkyl,

[0064] 3) is benzyl,

[0065] 4) is —C(O)—R¹⁰ or

[0066] 5) is —C(O)—O—R¹⁰,

[0067] R³ and R⁴ are identical or different and each is

[0068] 1) a hydrogen atom,

[0069] 2) (C₁-C₅)-alkyl,

[0070] 3) (C₁-C₅)-alkoxy,

[0071] 4) halogen,

[0072] 5) hydroxyl,

[0073] 6) —O—C(O)—R¹⁰ and R¹⁰ is as defined above, or

[0074] 7) R³ and R⁴ together form the radical —O—CH₂—O—,

[0075] R⁵ is

[0076] a) a hydrogen atom,

[0077] b) (C₁-C₅)-alkyl or

[0078] c) benzyl, and

[0079] R⁶, R⁷ and R⁸ are identical or different and each is

[0080] a) a hydrogen atom, or

[0081] b) has, in the case of i), the meaning of R² under items 2.1 to2.14, and

[0082] n is zero, 1 or 2,

[0083] m is zero, 1 or 2, the sum of n and m being 1, 2 or 3, or

[0084] where in the case ii)

[0085] R¹ is

[0086] 1) phenyl or

[0087] 2) phenyl, mono- to trisubstituted by R², where R² is as definedfor the case i) under items 2.1 to 2.15,

[0088] Q is the structural moiety X and

[0089] R⁶, R⁷ and R⁸ are identical or different and each is defined asabove,

[0090] n is 1 and

[0091] m is 1, or

[0092] where in the case iii)

[0093] R¹, Q, R⁶, R⁷ and R⁸ are identical or different and each has themeaning mentioned for the case ii),

[0094] m and n are zero, 1 or 2 and where the meanings of n and m arenot identical, and

[0095] X is

[0096] a) a covalent bond,

[0097] b) —O—,

[0098] c) —S—,

[0099] d) —S(O)—,

[0100] e) —S(O)₂—,

[0101] f) —C(O)— or

[0102] g) —C(OH)—, and

[0103] Y is

[0104] a) —O— or

[0105] b) —S—, and

[0106] A is HO—NH—C(O)— or HO—C(O)— and

[0107] B is

[0108] a) —(CH₂)_(q)—, where q is zero, 1, 2, 3 or 4, or

[0109] b) is —CH═CH—.

[0110] Preference is given to a compound of the formula I and/or aphysiologically tolerable salt of the compound of the formula I and/oran optionally stereoisomeric form of the compound of the formula I,where

[0111] R¹ in the case i) is a radical of the formula II or III and Q isthe structural moiety VI, VII, VIII or X,

[0112] R¹ in the case ii) is phenyl or phenyl, mono- to trisubstitutedby methoxy, and Q is the structural moiety X, or

[0113] R¹ in the case iii) is phenyl, Q is the structural moiety X, n iszero and m is 2, and

[0114] A is HO—NH—C(O)— or HO—C(O)—,

[0115] B is a covalent bond,

[0116] X is an oxygen atom or a covalent bond, and

[0117] R² is phenyl or phenyl substituted by

[0118] a) hydroxyl,

[0119] b) —O—R¹⁰, where R¹⁰ is (C₁-C₃)-alkyl or-benzyl,

[0120] c) (C₁-C₂)-alkyl,

[0121] d) fluorine or chlorine,

[0122] e) —CN,

[0123] f) —CF₃ or

[0124] g) NR¹³R¹⁴, where R¹³ and R¹⁴ are each (C₁-C₃)-alkyl,

[0125] R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are identical or different and each is

[0126] a) a hydrogen atom,

[0127] b) methoxy,

[0128] c) methylenedioxo,

[0129] d) amino or

[0130] e) hydroxyl.

[0131] Particular preference is given to the compounds

[0132]R-2-(biphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,

[0133]R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,

[0134]R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,

[0135]R-2-(4-phenoxybenzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,

[0136]R-2-(4-phenoxybenzenesulfonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,

[0137]R-2-(4-(4-dimethylaminophenoxy)benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid,

[0138]R-2-(4-dimethylaminobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,

[0139]R-2-(4-benzoylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,

[0140]R-2-(4-methoxybenzenesulfonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,

[0141]R-2-(4-methoxybenzenesulfonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,

[0142]2-(4-methoxybenzenesulfonyl)-6,7-propylene-1,2,3,4-tetrahydroisoquinoline-1-hydroxamicacid,

[0143]R-5-(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-hydroxamicacid,

[0144]R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamicacid,

[0145]R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamicacid.

[0146] Furthermore, particular emphasis is given to those compounds ofthe formula I where the central carbon atom between amino and acid groupis present as R enantiomer.

[0147] The term halogen is understood as meaning fluorine, chlorine,bromine or iodine. The term alkyl or alkoxy is understood as meaningradicals whose carbon chain may be straight-chain, branched or cyclic.Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles suchas cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0148] The “heterocycles of the formula V” include, for example,thiomorpholine, piperidine, morpholine or piperazine.

[0149] Suitable physiologically tolerable salts of the compound of theformula I are, for example, alkali metal, alkaline earth metal andammonium salts including those of organic ammonium bases or basic aminoacids.

[0150] The invention also provides a process for preparing the compoundof the formula I and/or a physiologically tolerable salt of the compoundof the formula I and/or an optionally stereoisomeric form of thecompound of the formula I which comprises

[0151] a) reacting an imino acid of the formula XI

[0152] where the radical Q and n and m are as defined in the formula Iwith a (C₁-C₄)-alcohol or a benzyl alcohol to give the compound of theformula XII

[0153] where R_(x) is (C₁-C₄)-alkyl or benzyl, or

[0154] b) reacting a compound of the formula XII prepared according toprocess a) with the compound of the formula XIII

[0155] where R¹ is as defined in formula I and R_(Z) is a chlorine atom,imidazolyl or —OH, in the presence of a base or, if appropriate, adehydrating agent to give a compound of the formula XIV

[0156] where Q, R¹, n and m are as defined in formula I and R_(x) is asdefined in formula XII, or

[0157] c) reacting a compound of the formula XII prepared according toprocess a) with a base and subsequently with a compound of the formulaXIII to give a compound of the formula XIV, or

[0158] d) reacting a compound of the formula XI with a compound of theformula XIII to give a compound of the formula XV

[0159] where Q, R¹, n and m are as defined in formula I, or

[0160] e) reacting a compound of the formula XIV to give a compound ofthe formula XV, or

[0161] f) reacting a compound of the formula XIV prepared according toprocess b) or c) with the hydroxylamine of the formula XVI

H₂N—OR_(y)   (XVI)

[0162] where R_(y) is a hydrogen atom or a protective group for oxygen,to give the compound of the formula I and, if appropriate, removing theprotective group for oxygen, or

[0163] g) reacting a compound of the formula XV prepared according toprocess d) or e) with the hydroxylamine of the formula XVI to give thecompound of the formula I, or

[0164] h) separating into the pure enantiomers a compound of the formulaI prepared according to process f) or g) which, owing to its chemicalstructure, exists in enantiomeric forms, by forming salts withenantiomerically pure acids or bases, chromatography using chiralstationary phases or derivatization by means of chiral enantiomericallypure compounds such as amino acids, separation of the resultingdiastereomers, and removal of the chiral auxiliary, or

[0165] i) isolating the compound of the formula I prepared according toprocesses f), g) or h) either in free form or, if acidic or basic groupsare present, converting it, if appropriate, into physiologicallytolerable salts.

[0166] In the case of the (C₁-C₄)-alcohols, the reaction according toprocess step a) is carried out under customary reaction conditions inthe presence of HCl gas or thionyl chloride. The preparation of thecorresponding benzyl esters of the formula XII is carried out in benzeneor toluene using the appropriate alcohol and an acid such asp-toluenesulfonic acid. Tert-butyl esters can be prepared, for example,by known processes using isobutene and sulfuric acid.

[0167] The reaction according to process step b) is carried out in thepresence of a basic compound such as N-methylmorpholine (NMM),N-ethylmorpholine (NEM), triethylamine (TEA), diisopropylethylamine(DIPEA), pyridine, collidine, imidazole or sodium carbonate in solventssuch as tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide, dioxane, acetonitrile, toluene, chloroform ormethylene chloride, or even in the presence of water. Preference isgiven to using the sulfonyl chlorides of the formula XIII in thepresence of NMM in THF.

[0168] The reaction according to process step c) is carried out in thepresence of a base such as KOH, LiOH or NaOH.

[0169] The reaction according to process step d) is carried out in anaqueous organic solvent system, preferably in THF and water in thepresence of a base such as sodium carbonate and the compound of theformula XIII. Furthermore, the reaction can be carried out in theabsence of solvent with or without base under reduced pressure, asobtained by use of an oil pump.

[0170] The hydrolysis of the compound of the formula XIV to give thecompound of the formula XV (process step e) is carried out, for example,basic, preferably acidic or, in the case of the benzyl derivatives, byhydrogen-olysis. In the case of basic hydrolysis, it is necessary tofree the carboxylic acid from the carboxylic acid salt by treatment withanother acid, for example dilute hydrochloric acid.

[0171] The reaction according to process step f) is carried out underthe conditions which are customary for the formation of carboxamides, ina suitable solvent, for example an alcohol or dimethylformamide.

[0172] For the reaction according to process step g), the carboxylicacids of the formula XV are activated. Activated carboxylic acids are,for example, acyl halides, acyl azides, mixed anhydrides and carbonates.Preference is given to acyl chlorides or fluorides, mixed anhydrides andcarbonates of pivaloyl chloride, ethyl, isopropyl or isobutylchloroformate; active esters such as cyanoethyl, o- or p-nitrophenyl,succinimido or phthalimido, and to the activated carboxylic acids whichare obtainable using coupling reagents such as diisopropylcarbodiimide(DIC), carbonyldiimidazole (CDI), dicyclo-hexylcarbodimide (DCC) orbenzotriazolyltetramethyluronium tetrafluoro-borate (TBTU), ifappropriate with addition of hydroxybenzotriazole (HObt) oroxohydroxybenzotriazine (HOObt), preferred solvents being aproticsolvents.

[0173] The starting materials and reagents employed can either beprepared by known processes, or they are commercially available.

[0174] Suitable imino acids of the formula XI where n and m are 1 its,for example, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-carboxylic acid oroptionally 1- or 3-substituted4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylic acids. Theyare preferably prepared by cyclizing the corresponding amino acids withformaldehyde in the presence of an acid such as hydrochloric acid orsulfuric acid using the method of Pictet-Spengler (see W. M. Whaley,Organic Reactions 6 (1951)151.

[0175] In the case that in the imino acid of the formula XI n is zeroand m is 2, it is possible to use, for example,1,2,3,4-tetrahydro-9H-pyrido(3,4-b)indol-1-carboxylic acid and6,7-propylene-1,2,3,4-tetraisoquinoline-1-carboxylic acid as startingmaterial. To prepare the latter compound, indane is Friedel-Craftsalkylated with phenylsulfonylarziridine. The cyclization of theresulting 4-(2-benzenesulfonamidoethyl)indane is carried out usingglyoxylic acid in HBr/glacial acetic acid; the subsequent cleavage ofthe benzenesulfonyl radical is carried out using iodine/red phosphorusin HBr/glacial acetic acid.

[0176] An example of the case where in the compound XI n is 1 and m iszero is indoline-2-carboxylic acid. It is prepared, for example, bycatalytic hydro-genation of indol-2-carboxylic acid. Furthermore,mention may be made of the cyclization of 2-chlorophenylalanine or2-hydroxy-3-(2-chlorophenyl)-propionic acid to give imino acids of theformula XI.

[0177] If compounds of the formula I permit diastereomeric orenantiomeric forms and are obtained as mixtures thereof in the synthesischosen, separation into the pure stereoisomers is possible either bychromatography over an optionally chiral carrier material or, if theracemic compound of the formula I or a compound of the formula XI iscapable of forming salts, by fractional crystallization of thediastereomeric salts formed with an optically active base or acid asauxiliary. Suitable chiral stationary phases for thin-layer- orcolumn-chromatographic separation of enantiomers are, for example,modified silica carriers (Pirkle phases) and high-molecular-weightcarbo-hydrates such as triacetylcellulose. For analytical purposes,gas-chromato-graphic methods using chiral stationary phases may also beused, after appropriate derivatization known to the person skilled inthe art. The enantiomers of racemic carboxylic acids are separated usingan optically active, usually commercially available base such as(−)-nicotine, (+)- and (−)-phenylethylamine, quinine bases, L-lysine orL- and D-arginine to form the diastereomeric salts, which differ insolubility. The less soluble component is isolated as a solid, the moresoluble diastereomer is recovered from the mother liquor, and the pureenantiomers are obtained from the resulting diastereomeric salts. Inbasically the same manner, the racemic compounds of the formula I whichcontain a basic group such as an amino group can be converted into thepure enantiomers using optically active acids such as(+)-camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L-lacticacid and (+) and (−)-mandelic acid. It is also possible to convertchiral compounds containing alcohol or amine functions into thecorresponding esters or amides using appropriately activated oroptionally n-protected enantiomerically pure amino acids, or,conversely, to convert chiral carboxylic acids into the amides usingcarboxyl-protected enantiomerically pure amino acids, or into thecorresponding chiral esters using enantiomerically purehydroxycarboxylic acids such as lactic acid. The chirality of theenantiomerically pure amino acid or alcohol radical can then be employedto separate the isomers by resolving the diastereomers that are nowpresent using crystallization or chromatography over suitable stationaryphases and then removing the chiral moiety which has been carried alongby means of suitable methods.

[0178] Acidic or basic products of the compound of the formula I may bepresent in the form of their salts or in free form. Preference is givento pharmacologically tolerable salts, for example alkali metal oralkaline earth metal salts or hydrochlorides, hydrobromides, sulfates,hemisulfates, all possible phosphates and salts of the amino acids,natural, bases or carboxylic acids.

[0179] Hydroxylamine can be employed in free form, obtainable fromhydroxylamine salts and a suitable base in solution or in O-protectedform, or in each case also in the form of its salts. The preparation offree hydroxylamine is known from the literature and can be carried out,for example, in alcoholic solution. Preference is given to using thehydrochloride together with alkoxides such as Na methoxide, potassiumhydroxide or potassium t-butoxide.

[0180] O-protected hydroxylamine derivatives preferably containprotective groups which can be removed under mild conditions. Particularpreference is given here to protective groups of the silyl, benzyl andacetal types. Particularly suitable for this purpose are theO-trimethylsilyl, O-tert-butyldimethylsilyl, O-benzyl, O-tert-butyl andthe O-tetrahydropyranyl derivative.

[0181] Starting materials and intermediates which are employed forpreparing the compound of the formula I may, if they contain functionalgroups such as hydroxyl, thiole, amino or carboxyl, for example in theradicals R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸, be employed in suitablyprotected form.

[0182] The introduction of protective groups is required in all thosecases where, in a desired chemical reaction, undesirable side-reactionsare to be expected at other locations than reaction centers (T. W.Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991).

[0183] The protective groups employed can be removed before or after theconversion of the compound of the formula XII into the compound of theformula I.

[0184] Particularly, suitable for use as auxiliaries and bases are:HObt, HOObt, N-hydroxysuccinamide (HOSu), TEA, NMM, NEM, DIPEA,imidazole. Preferred solvents for the reaction are: dichloromethane(DCM), THF, acetonitrile, N,N-dimethylacetamide (DMA), DMF andN-methylpyrrolidone (NMP).

[0185] The preferred temperatures are between −78° C. and +90° C.,depending on the boiling point and the nature of the solvent used.Particular preference is given to the temperature range from −20 to +30°C.

[0186] The preparation of physiologically tolerable salts from compoundsof the formula I which are capable of forming salts, including theirstereoisomeric forms, is carried out in a manner known per se. Thecarboxylic acids and hydroxamic acids form stable alkali metal, alkalineearth metal or optionally substituted ammonium salts with basic reagentssuch as hydroxides, carbonates, bicarbonates, alkoxides and ammonia ororganic bases, for example trimethyl- or triethylamine, ethanolamine ortriethanolamine or else basic amino acids, for example lysine, ornithineor arginine. If the compounds of the formula I have basic groups, it isalso possible to prepare stable acid addition salts by using strongacids. Suitable for this purpose are both inorganic and organic acids,such as hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, benzenesulfonic, p-toluenesulfonic,4-bromobenzenesulfonic, cyclohexylamidosulfonic,trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic ortrifluoroacetic acid.

[0187] The invention also relates to pharmaceuticals which contain aneffective amount of at least one compound of the formula I and/or of aphysiologically tolerable salt of the compound of the formula I and/oran optionally stereoisomeric form of the compound of the formula I,together with a pharmaceutically suitable and physiologically tolerableexcipient, additive and/or other active compounds and auxiliaries.

[0188] On account of the pharmacological properties, the compoundsaccording to the invention are suitable for the prophylaxis and therapyof all those disorders in the course of which is involved an increasedactivity of matrix-degrading metalloproteinases. These includedegenerative joint disorders such as osteoarthroses, spondyloses,chondrolysis after joint traumas or relatively long immobilization ofthe joint after meniscus or patella injuries or tears of the ligaments.Furthermore, these also include disorders of the connective tissue suchas collagenoses, periodontal disorders, wound healing disorders andchronic disorders of the locomotory apparatus such as inflammatory,immunologically or metabolically related acute and chronic arthritides,arthropathies, myalgias and disorders of the bone metabolism. Thecompounds of the formula I are also suitable for the treatment ofulceration, atherosclerosis and stenoses. The compounds of the formula Ifurthermore suppress the release of the cellular tumor necrosis factor(TNFα) to a considerable extent and are therefore suitable for thetreatment of inflammations, carcinomatous disorders, formation of tumormetastases, cachexia, anorexia and septic shock.

[0189] The pharmaceuticals according to the invention are in generaladministered orally or parenterally. Rectal or transdermaladministration is also possible.

[0190] The invention also relates to a process for the production of apharmaceutical, which comprises bringing at least one compound of theformula I into a suitable administration form using a pharmaceuticallysuitable and physiologically tolerable excipient and, if appropriate,other suitable active compounds, additives or auxiliaries.

[0191] Suitable solid pharmaceutical preparation forms are, for example,granules, powders, coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions and also preparations with protracted release ofactive compound, in whose preparation customary auxiliaries, such asexcipients, disintegrants, binders, coating agents, swelling agents,glidants or lubricants, flavorings, sweeteners and solubilizers areused. Frequently used auxiliaries which may be mentioned are magnesiumcarbonate, titanium dioxide, lactose, mannitol and other sugars, talc,lactoprotein, gelatin, starch, cellulose and its derivatives, animal andvegetable oils such as fish liver oil, sunflower, groundnut or sesameoil, polyethylene glycol and solvents such as, for example, sterilewater and mono- or polyhydric alcohols such as glycerol.

[0192] The pharmaceutical preparations are preferably prepared andadministered in dose units, each unit as active constituent containing aspecific dose of the compound of the formula I according to theinvention. In solid dose units such as tablets, capsules, coated tabletsor suppositories, this dose can be up to approximately 1000 mg, butpreferably approximately 50 to 300 mg, and in injection solutions inampcule form up to approximately 300 mg, preferably approximately 10 to100 mg.

[0193] For the treatment of an adult patient weighing approximately 70kg—depending on the efficacy of the compounds according to formula I,daily doses of approximately 20 mg to 1000 mg of active compound,preferably approximately 100 mg to 500 mg, are indicated. Under certaincircumstances, however, higher or lower daily doses may be appropriate.The daily dose can be administered both by single administration in theform of an individual dose unit or else of several smaller dose unitsand by multiple administration of subdivided doses at specificintervals.

[0194]¹H-NMR spectra have been recorded on a 200 MHz apparatus fromVarian, in general using tetramethylsilane (TMS) as an internal standardand at room temperature (RT). The solvents used are indicated in eachcase. Generally, final products are determined by mass spectroscopicmethods (FAB-, ESI-MS). Temperature data in degrees Celsius, RT meansroom temperature (22° C.-26° C.). Abbreviations used are eitherexplained or correspond to the customary conventions.

PREPARATION EXAMPLES

[0195] The preparation of the compounds 1-12, 14-23, 27, 30 and 33 inTable 1 was carried out similarly to the procedures given in Examples13, 24-26, 28, 29, 31 and 32.

[0196] In Examples 4 to 9, a sulfonation was initially carried out,using p-(Ex. 4,6,9) or m-(Ex. 5,7,8) nitrobenzenesulfonyl chloride asdescribed under “Tic-sulfonation” (see Example 13). Subsequently, thehydrogenation of the nitro group was carried out under standardconditions known to the person skilled in the art, using hydrogen underatmospheric pressure and 10% Pd on activated carbon in methanol to givethe amine.

[0197] In all cases, it is also possible to employ the Tic benzyl esterdescribed under Example 13 for the sulfonation. In the subsequenthydrogenation, cleavage of the benzyl ester and reduction to give theamine occur simultaneously. The identical products which are obtained inboth cases, p- or m-aminobenzenesulfonyl Tic are subsequently reactedfurther as follows:

Example 4

[0198] Initially, acetylation under standard conditions(triethylamine/DMAP/acetic anhydride) is carried out; the N-acetylcompound, which is obtained in good yield, is subsequently reactedfurther to give the hydroxamic acid, as described in Example 25.

Examples 5 and 6

[0199] To prepare the hydroxamic acid, the p-aminobenzenesulfonyl-Tic isactivated in the same manner as described in Example 13, except thatdouble the amount of ethyl chloroformate and N-methylmorpholine isemployed. Irreversible N-ethoxycarbonylation takes place in one step,together with the activation of the carboxylic acid.

Examples 7, 8 and 9

[0200] The p- or m-aminobenzenesulfonyl-Tic described above is acylatedunder the Schotten-Baumann conditions known to the person skilled in theart. For this purpose, use is made of: Ex. 7: salicyloyl chloride,Example 8: p-methoxybenzoyl chloride, Example 9: benzyl chloroformate.The further reaction to give the hydroxamic acid is carried out asdescribed in Example 25.

Example 13

[0201]R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid

[0202] General Procedure:

[0203] Tic benzyl ester p-toluenesulfonate 1 mol of Tic (free aminoacid), 10 moles of benzyl alcohol and 1 mol of p-toluenesulfonic acidmonohydrate are dissolved or suspended in 1.2 l of toluene and heatedunder reflux using a water separator. After the reaction has ended, thesolvent is evaporated and the solid crystalline residue is repeatedlytaken up in diethyl ether and filtered off with suction and subsequentlydried using oil pump vacuum. Yield: quantitative.

[0204]¹H NMR: (200 MHz, δ in ppm, DMSO-d₆) 9.7 (s, brd., 2 H, prot.NH),7.5−7.25 (2 m, 7H, arom.), 7.1 (d, 2H, arom. p-TsOH), 5.3 (s, 2H, CH₂benzyl); 4.7 (dd, 1H, CHα); 4.4 “d”, 2H, CH₂); 3.4−3.1 (m, 2H, CH₂); 2.3(s, 1H, CH₃ p-TsOH).

[0205] Tic Sulfonation

[0206] At 0° C., 1.0 mol of Tic solution (free amino acid 17.7 g) in 50ml of 2 N aqueous NaOH is admixed with finely powdered sulfonyl chloride(105 mmol), followed by 14.2 g (110 mmol) of diisopropylethylamine and50 ml of acetone or THF. The ice bath is removed after 10 min and themore or less homogeneous solution is stirred at RT for a further 6 h.The reaction mixture is subsequently concentrated, admixed with 300 mlof ethyl acetate and acidified with 4 N HCl. The organic phase isseparated off and the aqueous phase is extracted two more times with ineach case 50 ml of ethyl acetate. The combined organic phases areextracted with saturated NaCl solution and dried over sodium sulfate.The solvent is distilled off and the sulfonatedtetrahydroisoquinolinecarboxylic acid remains as an oily or solidresidue which in some cases may be purified by recrystallization fromethyl acetate/petroleum ether, but which frequently is sufficiently purefor further reaction.

[0207] 13a MethylR-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroiso-quinoline-3-carboxylate

[0208] A solution of 1.92 g (0.01 mol) of methylR-1,2,3,4-tetrahydroisoquinoline-3-carboxylate and 2.7 g (0.01 mol) of4-phenoxybenzenesulfonyl chloride in 50 ml of absolute THF are heatedunder reflux in the presence of 1.7 ml (0.01 mol) of N-ethylmorpholinefor 8 h. The solvent is removed, the residue is taken up indichloromethane and the solution is extracted successively with 5%citric acid, 5% sodium bicarbonate solution and 2× with water. Theorganic phase is dried over sodium sulfate and concentrated to give theester which is subjected to further reactions without purification.

[0209] Yield: 4.0 g (95% of theory) of 13a.

[0210] 13b R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0211] At room temperature, a solution of 4.0 g (9.5 mmol) of the ester(13a) in 50 ml of isopropanol is stirred after addition of 9.5 ml of 1 Naqueous sodium hydroxide solution for 24 h. The mixture is thenacidified with 1 N hydrochloric acid and evaporated to dryness underreduced pressure. The residue is taken up in toluene, the solution isextracted with 5% citric acid and the organic phase is dried over sodiumsulfate and concentrated under reduced pressure.

[0212] Yield: 3.4 g of carboxylic acid 13b (83% of theory)

[0213] Melting point: 147° C.

[0214] 13cR-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid

[0215] 3.4 g (8.3 mmol) of the carboxylic acid 13b are dissolved in 30ml of DMF and, at −20° C., admixed successively with 1.4 g (12 mmol) ofN-ethyl-morpholine and 1.13 g (8.3 mmol) of isobutyl chloroformate.After an activation time of 30 min, the mixture is admixed with 4.37 g(41.5 mmol) of O-trimethylsilylhydroxylamine and stirred at roomtemperature for a further 4 h. 250 ml of ethyl acetate and 500 ml ofwater are added to the mixture which is then acidified with citric acid.The organic phase is separated off and the aqueous phase is extracted4×, and the combined organic phases are dried over sodium sulfate andconcentrated under reduced pressure. Recrystallization fromtoluene/ethyl acetate (1:1) affords the title compound 13.

[0216] Yield: 2.9 g (82% of theory) Melting point: 170° C.(decomposition)

Example 17

[0217] Trans-beta-styrenesulfonyl chloride is employed for thesulfonation of the Tic benzyl ester under standard conditions (seeExample 13). In the subsequent hydrogenation (H2, Pd/C), debenzylationand hydrogenation of the double bond are effected in one step.Subsequently formation of the hydroxamic acid by the method of Example25.

Examples 20, 21 and 22

[0218] The starting material is commercially available 7-hydroxy-Tic.This is sulfonated under standard conditions according to processvariant d). This gives, after customary work-up, a mixture of 2- and7-disulfonated and exclusively 2-sulfonated 7-hydroxy-Tic. However, atthis stage it is not necessary to separate the two compounds. Directfurther conversion to give the hydroxamic acid is carried out understandard conditions. As expected, partial ethoxycarbonylation of the7-hydroxyl group takes place during the activation. The hydroxamic acidproduct mixture therefore contains all three products which can beseparated by chromatography over silica gel 60, preparative thin-layerchromatography or HPLC.

Example 23

[0219] The starting material for the preparation of 7-nitro-Tic isenantiomerically pure commercial (R)-Tic-OH or (S)-Tic-OH. The7-nitro-Tic is prepared according to E. D. Bergann, J. Am. Chem. Soc.74, 4947 (1952) or according to E. Erienmever, A. Lipp, Liebigs Ann.Chem. 219, 218 (1983) by nitration with nitrating acid. A mixture of the6- and 7-nitro isomers is formed, and the reaction mixture additionallycontains unnitrated starting materials. Prior to the separation, themixture is initially sulfonated under standard conditions. The resultingmixture of the three sulfonamides can then be chromatographed oversilica gel 60. Successively, mixed fractions containing educt/6-nitro-and 6-nitro-/7-nitro-(4-methoxybenzenesulfonyl)-Tic are obtained;finally, fractions of pure 7-nitro compound are eluted. This can befurther converted into the hydroxamic acid, in a customary mannersimilar to Example 25.

Example 24

[0220]2-(4-Methoxybenzenesulfonyl)-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid

[0221] The preparation of the corresponding benzyl carboxylate from thecarboxylic acid corresponds to the general procedure (see Example 13).Sulfonation or benzyl ester cleavage is carried out similarly to Example25a. The reaction of the free sulfonated carboxylic acid is carried outas described under 25b.

[0222] After treatment with diethyl ether, the product is obtained incrystalline form. Yield: 140 mg, 57% of theory; melting point 166° C.

Example 25

[0223]2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid

[0224] 25a2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

[0225] The preparation of the benzyl ester is carried out according tothe general procedure (see Example 13). For the sulfonation, 1.2 g (3.05mmol) of the benzyl ester are employed. This is dissolved in 20 ml ofTHF and, at 0° C., admixed with 0.63 g (3.05 mmol) of4-methoxybenzenesulfonyl chloride. 0.32 ml of N-methylmorpholine areadded and the reaction mixture is stirred at 0° C. to room temperatureovernight. The mixture is subsequently admixed with 20 ml of ethylacetate and extracted with 10% strength sodium carbonate solution andsaturated NaCl solution. The organic phase is dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue thatremains is subjected to chromatography under pressure over silica gel 60using ethyl acetate/petroleum ester/glacial acetic acid 20/10/1. Pureproduct fractions (600 mg) are combined and, after concentration,directly hydrogenated using 100 mg of 10% Pd/C in 50 ml of ethanol.After the reaction has ended, the catalyst is separated off and theremaining solution is concentrated under reduced pressure. This gives330 mg (66% of theory).

[0226] 25b2-(4-Methoxybenzenesulfonyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid

[0227] 330 mg (0.75 mmol) of the carboxylic acid from Example 25a aredissolved in 15 ml of THF and, at −20° C., admixed successively with0.07 ml (0.75 mmol) of ethyl chloroformate and 0.15 ml (1.5 mmol) ofN-methylmorpholine (NMM). After 30 min at this temperature, the mixtureis mixed with 0.474 ml of O-trimethylsilylhydroxylamine (3.75 mmol).After 6 h at RT, 30 ml of ethyl acetate are added to the mixture whichis then extracted with 20% strength aqueous citric acid and saturatedNaCl solution. The organic phase is dried over sodium sulfate andconcentrated under reduced pressure, leaving 290 mg of a clear viscousoil which crystallizes on treatment with diethyl ether.

Example 26

[0228]2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid

[0229] 26a Methyl2-(morpholihosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

[0230] With stirring, 4.2 g (0.025 mol) of morpholine-N-sulfonylchloride in 20 ml of THF are added dropwise to a solution of 4.8 g(0.025 mol) of methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate and2.9 g (0.025 mol) of N-ethylmorpholine. The mixture is stirred at RT for2 h and then heated under reflux for another 2 h so that the reactiongoes to completion. CHCl₃ is added to the reaction solution, which isthen treated with 5% strength citric acid, 5% strength NaHCO₃ solutionand water. The organic phase is dried over Na₂SO₄ and evaporated todryness. Yield of ester (26a): 7.5 g (92% of theory)

[0231] 26b2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0232] Reaction of 7.5 g (0.023 mol) of 26a by the method of 13b.

[0233] Yield of carboxylic acid 26b: 6.7 g (93% of theory)

[0234] 26c2-(Morpholinosulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid

[0235] 2.3 g (7.5 mmol) of the carboxylic acid 26b are dissolved in 40ml of absolute THF and, at −20° C., admixed successively with 1.2 g (12mmol) of N-methylmorpholine and 1.1 g (7.5 mmol) of isobutylchloroformate. After 30 min, the mixture is admixed with 3.9 g (37.5mmol) of O-trimethylsilylhydroxylamine and stirred at RT for a further 5h. 200 ml of water are added and the mixture is acidified with diluteHCl and extracted repeatedly with dichloromethane. The pooled organicphases are dried over Na₂SO₄ and concentrated under reduced pressure.The resulting oil is chromatographed under pressure over silica gel 60using ethyl acetate/dichloromethane (1:1) as mobile phase.Recrystallization of the product fractions from ethyl acetate gavecrystalline hydroxamic acid 26c.

[0236] Yield: 1.4 g (55% of theory) Melting point: 164-165° C.(decomposition)

Example 28

[0237] 1-(4-Methoxybenzenesulfonyl)indoline-2-hydroxamic acid

[0238] 28a 1-(4-Methoxybenzenesulfonyl)indoline-2-carboxylic acid

[0239] At 50° C. and 0.02 mbar, 1 g (6.1 mmol) of indoline-2-carboxylicacid and 2.5 g (12.2 mmol) of 4-methoxybenzenesulfonyl chloride are keptfor 4 hours (h) in a kugelrohr which is rotated slowly and continuously.The brown crystalline product is subsequently taken up in sodiumcarbonate solution and extracted twice with diethyl ether. The aqueousphase is acidified using 6 N HCl and extracted four times with ethylacetate. The combined organic phases are extracted with saturated NaClsolution, dried over sodium sulfate and concentrated under reducedpressure. Residual solvent is removed using oil pump vacuum.

[0240] Yield: 1.34 g, (65% of theory)

[0241]¹H-NMR: (DMSO-d₆) 7.8; 7.1 (2 d, 4H, arom. p-TsOH); 7.4−7.0 (m,4H, arom.); 4.9 (dd, 1H, CHα); 3.8 (2, 3H, OMe); 3.4−2.9 (2 dd, 2H, CH₂)

[0242] 28b 1-(4-Methoxybenzenesulfonyl)indoline-2-hydroxamic acid

[0243] 1.3 g (3.9 mmol) of the1-(4-methoxybenzenesulfonyl)indoline-2-carboxylic acid of Example 28aare dissolved in 10 ml of N,N-dimethylacetamide (DMA) and, at −20° C.,admixed successively with 0.37 ml (1 equivalent) of ethyl chloroformateand 0.81 ml of N-methylmorpholine. After an activation time of 30minutes (min), the mixture is admixed with 3.8 ml (19.5 mmol) ofO-trimethylsilylhydroxylamine and stirred at RT for a further 4 h. Themixture is diluted with ethyl acetate, acidified with citric acid and,after removal of the aqueous phase, washed with saturated NaCl solution.The organic phase is dried over sodium sulfate, filtered off andconcentrated under reduced pressure. The resulting oil is subjected tochromatography under pressure over silica gel 60 usingdichloromethane/ethyl acetate/acetic acid 5.5/3.5/1 as mobile phase.Product fractions (showing positive iron(III) chloride-reaction) arepooled and concentrated. The crystalline product is subsequently admixedwith diethyl ether and freed of residual solvent under reduced pressure.

[0244] Yield: 400 mg (33% of theory) Melting point: 142° C.

Example 29

[0245]R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-hydroxamicacid hydrochloride

[0246] 29a:R-3,5-di(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylicacid

[0247] With ice-cooling, 15 ml of 2 N NaOH and 4.5 g (42 mmol) of sodiumcarbonate are added successively to a solution of 6.1 g (30 mmol) of4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylic acidhydro-chloride in 50 ml of water. With stirring, 13.7 g (67 mmol) of4-methoxybenzenesulfonyl chloride in 40 ml of ether are added. Thereaction mixture is stirred at RT for a further 24 hours and then withice-cooling adjusted to pH 3-4 using 5 N HCl and extracted with ethylacetate. The organic phase is dried over sodium sulfate, filtered andconcentrated to dryness to give 11.9 g (78% of theory) of the desiredproduct in the form of an oil.

[0248] 29b:R-5-(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-carboxylicacid hydrochloride

[0249] With ice-cooling and stirring, 23.5 ml each of a 1 N NaOHsolution are added dropwise in intervals of 1 hour to a solution of 11.0g (24 mmol) of disulfonated intermediate in 300 ml of methanol. After 6hours, a final 15 ml of 1 NaOH are added and the mixture is stirred atRT overnight. The methanol is removed under reduced pressure and themixture is then adjusted to pH 5 using 5 N HCl. The precipitatedcrystals are filtered off with suction and dried under reduced pressureover P205.

[0250] Yield: 5.2 g (60% of theory) of 29b

[0251] Melting point: 264-265° C. (decomp.)

[0252] 29c:R-5-(4-methoxybenzenesulfonyl)-4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-hydroxamicacid hydrochloride

[0253] 8.0 g (24 mmol) of compound 29b in 60 ml of DMF are admixed with4.27 g (24 mmol) of tetramethylammonium hydroxide and then, at 0° C.,with 2.7 g (24 mmol) of N-ethylmorpholine and, a little at a time, with5.2 g (24 mmol) of di-tert-butyl dicarbonate. The reaction mixture isstirred overnight, poured onto ice-water, adjusted to pH 5 using diluteHCl and extracted repeatedly with ethyl acetate. After removal of thesolvent, the combined dried organic phase affords 10.5 g ofBOC-protected 29b which is used directly for preparing the hydroxamicacid.

[0254] To this end, 10.5 g (23 mmol) of the above compound are dissolvedin 150 ml of absolute THF and, at −20° C., admixed with 4.4 g (38 mmol)of N-ethylmorpholine and 3.4 g (25 mmol) of isobutyl chloroformate. Themixture is stirred for 1 hour, after which 10.9 g (0.1 mol) ofO-trimethylsilylhydroxylamine are added, the temperature being kept at−20° C. for 1 hour. After a further 4 hours of stirring at RT, thereaction mixture is adjusted to pH=1 using 1N HCl, admixed with 300 mlof water and extracted repeatedly with dichloromethane. The combinedorganic phases are dried over sodium sulfate and concentrated to drynessunder reduced pressure.

[0255] To cleave the BOC protective group, 8.1 g of the remaining oilare taken up in 50 ml of dichloromethane and 25 ml of trifluoroaceticacid are added dropwise at 0° C. The reaction mixture is stirred at RTfor 4 hours and then concentrated under reduced pressure. The residue isdigested with dichloromethane and then dissolved in 0.1 N HCl, filteredand freeze-dried.

[0256] Yield of hydroxamic acid 29: 5.2 g (56% of theory)

[0257] Melting point: 110° C.

Example 31

[0258]R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole-3-hydroxamicacid

[0259] 31 aR-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole-3-carboxylicacid

[0260] A solution of 2.16 g (10 mmol) of1,2,3,4-tetrahydro-9H-pyrido-(3,4-b)-indole-3-carboxylic acid in amixture of 10 ml of acetone and 10 ml of water is, after addition of10.5 ml of 2 N NaOH, admixed with stirring with 2.06 g (10 mmol) of4-methoxybenzenesulfonyl chloride. The solution is stirred at roomtemperature for 18 hours, the acetone is removed and the pH is adjustedto 1 using concentrated HCl. The resulting precipitate is filtered off,washed with water and dried.

[0261] Yield: 2.7 g of carboxylic acid 31a (85% of theory)

[0262] Melting point: 232-234° C.

[0263] 31bR-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-hydroxamicacid

[0264] 2.5 g (7.4 mmol) of the, carboxylic acid 31a are dissolved in 40ml of absolute DMF and, at −20° C., admixed successively with 1.4 ml (12mmol) of N-ethylmorpholine and 0.97 ml (7.4 mmol) of isobutylchloroformate. After an activation time of 30 min, 4.53 ml (37 mmol) ofO-trimethylsilylhydroxylamine are added and the mixture is subsequentlystirred at room temperature for 19 hours. The mixture is adjusted topH=3.5 using citric acid and then extracted repeatedly with ethylacetate. The combined organic phases are dried over sodium sulfate,concentrated under reduced pressure and purified by silica gelchromatography using methylene chloride/methanol (95:5).

[0265] Yield: 2.4 g of hydroxamic acid (91.5% of theory)

[0266] Melting point: 87° C.

Example 32

[0267]R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-hydroxamicacid

Preparation by the Method of Example 31

[0268] Melting point: 110-111° C.

Example 33

[0269]R-2-(4-morpholinobenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)-indole-3-hydroxamicacid

Preparation by the Method of Example 31

[0270] Melting point: 125° C. (decomposition)

Example 42

[0271]R-2-[4-(4-chlorophenoxy)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

[0272] 8.2 g (46.4 mmol) ofR-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are admixed with 46.4ml of 1 N NaOH and 50 ml of acetone and dissolved in water. At −5° C.and with stirring, 14.1 g (46.4 mmol) of4-(4-chlorophenyloxy)benzenesulfonyl chloride in 50 ml of THF are addeddropwise and, after half has been added, the reaction mixture is admixedwith 0.6 g (46.4 mmol) of diisopropylethylamine. The mixture is stirredovernight, the precipitate is filtered off and the filtrate is adjustedto pH=3 using 2 N HCl and extracted repeatedly with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andevaporated to dryness under reduced pressure. Recrystallization fromtoluene and drying under reduced pressure gives the title compound.

[0273] Yield: 16.1 g (78% of theory) Melting point: 168-169° C. TABLE 1Hydroxamic acids of the formula I Ex- ample mp. No. Structure (° C.)Solvent ¹H NMR 1

DMSO-d6 2.7-3.1(m, 2H) 4-4.7(2m, 2H) 7-7.8(3m, 9H) 9.5; 10.6(2s, br, 2H)2

94 Decomp. CDCL₃ 2.65-2.8(m, 1H); 3.1-3.25(m, 1H); 4.35-4.75(m, 3H);6.9-7.2(m, 4H); 7.3-7.65(m, 7H); 7.8(d, 2H) 3

DMSO-d6 2.9(m, 2H); 4.5(t, 1H); 4.6(m, 2H); 7.0-7.9(m12H); 9.9(s, 1H);10.8 (s, 1H) 4

DMSO-d6 2.1(s, 3H) 2.8-3.5 (2m; 2H), 4.3-4.6 (m, 3H), 7.1; 7.7 (2m, 8H)8.65; 8.85; 10.3; 10.8 (4s, 2h) 5

DMSO-d6 1.2(t, 3H) 2.85 (m, brd, 2H) 4.15 (q, 2H) 4.4-4.7(m, 3H) 7.1(m,brd, 4H) 7.4(m, 2H) 7.6(m, 2H) 8; 9.9; 10.7(3s, 3H) 6

DMSO-d6 1.2(t, 3H) 2.8(m, brd, 2H) 4.15(q, 2H) 4.3-4.6(m, 3H) 7.1(m,brd, 4H) 7.55; 7.7(2d, 4H) 8.7; 9.5(2s, 3H) 7

DMSO-d6 2(s, 3H) 2.9(m, 2H) 4.4-4.6(2m, 3H) 7.1; 7.5; 7.9; 8.3(4m, 14H)8

DMSO-d6 2.85(m, 2H) 3.85 (s, 3H) 4.4-4.7 (2m, 3H) 7.1; 7.4; 7.6; 8(4m,13H) 8.9; 10.8(2s, 2H) 9

DMSO-d6 3(m, 2H) 4.4-4.8 (m, 3H) 5.2(s, 3H) 7.1-7.5(2m, 9H) 7.55;7.8(2d, 4H) 8.8; 10.7(2s, 2H) 10

175 Decomp. DMSO-d6 2.7-3.0(m, 2H); 3.25(m, 4H); 3.75(m, 4H); 4.45(t,1H); 4.5(M, 2H); 6.9-7.65(m, 8H) 11

DMSO-d6 2.7-3.1(m, 2H) 4.5-4.8(m, 3H) 6.8-7.2(m, 4H) 7.7(m, 3H)7.9-8.2(m, 3H) 8.5(s, 1H) 12

DMSO-d6 2.8(s, 6H) 2.95 (d, brd, 2H) 4.4-4.8m, 3H) 7.1(m, 4H) 7.25(d,1H) 7.6(dd, 2H) 8.2 (“t”, 2H) 8.5(d, 1H) 8.9; 10.7(2s, 2H) 13c

170 Decomp. DMSO-d6 2.9(d, 2H); 4.4(m, 2H); 4.55(d, 1H); 6.9-7.85(m,13H); 8.9(s, 1H); 10.75(s, 1H); 14

DMSO-d6 2.9(m, 2H); 3.64(s6H); 4.38(t, 1H); 4.5(m, 2H); 6.75-7.75(m,12H); 15

DMSO-d6 2.85(m, 2H); 4.45(t, 1H); 4.63(m, 2H); 6.9-8.7(m, 11H); 9.9(s,1H); 10.8(s, 1H); 16

DMSO-d6 2.9-3.1(m, 2H) 3.9-4.6(2m, 5H) 7.15(m, 4H) 7.3 (m, 5H) 8.85;10.6 (2s, 2H) 17

DMSO-d6 2.8-3.6(m, 6H) 4.5-4.7(m, 3H) 7.1-7.4(m, 9H) 8.7; 8.9; 9.5; 10.7(4s, 2H) 18

DMSO-d6 2.95(m, 2H); 4.5(t, 1H); 4.62(m2H); 7.0-8.05(m, 13H); 19

DMSO-d6 2.85(m, 2H); 4.4(M, 1H); 4.53(m, 2H); 6.95-7.8(M; 13H); 20

DMSO-d6 2.8(m, 2H) 3.8(s, 3H) 4.35-4.6(m, 3H) 6.9-7.2; 7.6-7.8(2m; 7H)8.9; 10.8(2s, 2H) 21

DMSO-d6 1.3(t, 3H) 2.85 (m, 2H) 3.8(s, 3H) 4.0-4.6(m, 5H) 6.9-7.1;7.6-7.8(2m, 7H) 8.8; 10.8(2s, 2H) 22

DMSO-d6 2.8(m, 2H) 3.8(s, 3H) 3.9(s, 3H) 4.35-4.6(m, 3H) 6.9-7.2;7.6-7.8 (2m, 11H) 8.9; 10.9(2s, 2H) 23

DMSO-d6 3.0(m, 2H) 3.8(s, 3H) 4.4-4.8(m, 3H) 6.95; 7.7(2d, 4H) 7.4(d,1H) 7.95 (dd, 1H) 8.05(d, 1H) 8.95; 10.8(2s, 2H) 24

166 DMSO-d6 2.7(m, 2H) 3.8(s, 3H) 4.2-4.5(m, 3H) 5.9; 6.7; 7.0; 7.7(4d,6H) 8.85; 10.7(2s, 2H) 25

DMSO-d6 2.8(m, 2H) 3.65-3.65(4s, 12H) 4.3-4.5(m, 3H) 6.5(s, 1H) 7.0;7.7(2d, 4H) 8.8; 10.7(2s, 2H) 26

165 DMSO-d6 2.9-3.35(m, 6H); 3.45-3.65(m, 4H); 4.38(m, 1H); 4.5;4.65(AB, 2H); 7.2 (s, 4H); 8.9(s, 1H); 10.65(s, 1H) 27

DMSO-d6 1.95(m, 2H); 2.5-2.95 m, 7H); 3.4 (m, 1H); 3.8(s, 3H);3.8-4.1(m, 1H); 6.9-7.1(m, 4H); 7.7 (d, 2H); 9.0-11.1 (2s, 2H); 28

142 DMSO-d6 2.8-3.2(m, 2H) 3.8(s, 3H) 4.6 (dd, 1H) 7.0-7.8 (3m, 8H) 9.1;10.9(2s 2H)

NOT TO BE TAKEN INTO CONSIDERATION FOR THE PURPOSES OF INTERNATIONALPROCESSING

[0274] TABLE 2 Carboxylic acids of the formula I mp. Ex. Structure (°C.) ¹H NMR 34

205 (in CDCl3); 3.0-3.25 (m, 2H); 4.48(d, 1H); 4.65(d, 1H); 4.9-5.0 (m,1H); 6.97-7.18 (m, 4H); 7.38-7.7(m, 7H); 7.85(d, 2H) 35

207-209 (in DMSO-d6); 3.05-3.15(m, 2H); 4.45-4.7(d, d, 2H); 4.9(m, 1H);7.1-8.0 (m, 12H); 12.8(s, 1H); 36

3.1(m, 2H); 4.6(m, 2H); 4.90(d, 1H); 7.0-8.0(2m, 12H) 37

3.0-3.2(m, 2H); 4.55 (dd, 2H); 4.90(d, 1H); 7.05-7.25(m, 4H);7.1-8.0(3m, 12H) 38

3.0-3.2(m, 2H); 4.55 (dd, 2H); 4.90(d, 1H); 7.05-7.25(m, 4H);7.1-8.0(3m, 12H) 39

122-135 amor- phous (in MeOH-d4); 3.02-3.36(m, 2H u. s, 6H); 4.57(d,1H); 4.72(d, 1H); 4.85-5.01(m, 1H); 7.03-7.19(m, 4H); 7.54(d, 2H);7.7-7.98(m, 6H) 40

2.9-3.2(m, 2H); 3.8 (s, 3H); 4.3-4.6(dd, 2H); 4.8(m, 1H); 7.1 (m, 6H);7.8(d, 2H) 41 13b

147 (in DMSO-d6); 3.0-3.15(m, 2H); 4.4-4.65(d, d, 2H); 4.6-4.9 (m, 13H);12.9(s, 1H); 42

167-168 (in DMSO-d6); 3.0-3.15(m2H); 4.4-4.65(m, 2H); 4.85 (m, 1H);7.0-7.9 (m, 12H); 12.9(s, 1H); 43

oil (in DMSO-d6); 2.4-2.7 (m, 6H) 2.8-3.0(m, 2H); 3.3-3.5(m, 6H);4.4-4.6(m, 2H); 4.7(m, 1H); 7.0-7.9(m, 13H) 44

(in DMSO-d6); 2.9-3.2(m, 2H); 4.4-4.65 (d, d, 2H); 4.85(m, 1H); 5.15(s,2H); 7.0-7.9 (m, 12H); 12.9(s, 1H); 45

oil (in DMSO-d6); 3.0-3.2(m, 2H); 4.4-4.75(d, d, 2H); 4.9(m, 1H);7.1-8.1(m, 13H); 12.9(s, 1H); 46

218-219 (in DMSO-d6); 3.0-3.1(m, 2H); 4.45-4.8(d, d, 2H); 4.9-5.0(m,1H); 7.0-8.8(m, 1H); 12.8(s, 1H); 47

211-213 amor- phous 3.0-3.2(m, 2H); 4.5 (d, 1H); 4.72(d, 1H);4.9-5.05(m, 1H); 7.05-7.25(m, 4H); 7.6-7.75(m, 3H); 7.85-8.05(m, 2H);8.2-8.4(m, 3H); 12.9 (sb, 1H) 48

3.0; 3.2(2m, 4H); 3.3-3.6(m, 2H); 4.5-4.75(dd, 2H); 4.8 (“t”, 1H);7.1-7.4(m, 9H) 49

3.0-3.3(m, 2H); 3.8 (s, 3H); 4.45-4.85 (dd, 2H); 4.85(m, 1H); 7.0; 7.4;7.8(3d, 5H); 8.0(dd, 1H); 8.1 (d, 1H) 50

3.3(m, 2H); 4.5-4.85 (dd, 2H); 5.05(m, 1H); 7.2-8.1(mm, 11H) 51

3.3(m, 2H); 4.5-4.8 (dd, 2H); 5.05(dd, 1H); 7.2-8.0(4m, 11H) 52

3.1-3.4(m, 2H); 4.5-5.0(dd, 2H); 4.95 (m, 1H); 7.2-8.1 (2m, 11H) 53

3.1-3.4(m, 2H); 4.5-4.9(dd, 2H); 4.95 (m, 1H); 7.2-8.15 (2m, 11H) 54

226-228 (in DMSO-d6); 2.8-3.1(m, 2H); 4.3-4.5 (d, d, 2H); 4.75(m, 1H);5.95(s, 2H); 6.7-7.9(m, 11H); 12.9(s, 1H); 55

2.9-3.1(m, 2H); 3.8 (s, 6H); 4.35-4.6(dd, 2H); 4.90(d, 1H); 6.7; 6.8(2s,2H); 7.55; 7.80(2d, 4H); 7.9(m, 4H) 56

2.8-3.1(m, 2H); 4.3-4.6(dd, 2H); 4.85 (m, 1H); 6.5(m, 2H); 6.95(d, 1H);7.5-8.0 (m, 8H); 8.5; 8.8(2s, 1H) 57

115 (in DMSO-d6); 3.3-3.45(m, 2H); 4.4-4.65 (m, 2H); 5.8-5.9(m, 1H);6.85-7.9(m, 13H); 10.7(s, 1H); 58

3.1; 3.4(2m, 2H); 5.05(m, 1H); 7.0-8.0 (m, 12H) 59

2.8-3.0(m, 2H); 3.5-3.8(m, 2H); 4.3 (s, 1H); 7.1-8.0 (mm, 12H) 60

2.7-2.9(m, 2H); 3.4-3.8(m, 2H); 3.8 (2s, 6H); 5.4(s, 1H); 6.7; 6.9(2s,2H); 7.55; 7.80(2d, 4H); 7.9(s, 4H)

Pharmacological Examples

[0275] Preparation and, determination of the enzymatic activity of thecatalytic domains of human stomelysine and of neutrophil collagenase.

[0276] The two enzymes were prepared according to Ye et al.,(Biochemistry 31 (1992) 11231-5). To measure the enzyme activity orenzyme inhibitor action, 70 μl of buffer solution and 10 μl of enzymesolution are incubated for 15 minutes with 10 μl of a 10% strength (v/v)aqueous dimethyl sulfoxide solution, which optionally contains theenzyme inhibitor. After addition of 10 μl of a 10% strength (v/v)aqueous dimethyl sulfoxide solution which contains 1 mmol/l of thesubstrate, the enzyme reaction is monitored by fluorescence spectroscopy(328 nm (ex)/393 nm(em)). The enzyme activity is shown as extinctionincrease/minute. The IC50 values listed in Table 3 were determined asthe inhibitor concentration which leads to a 50% inhibition of theenzyme. The buffer solution contains 0.05% of Brij (Sigma, Deisenhofen,Germany) and also 0.1 mol/l of tris/HCl, 0.1 mol/l of NaCl, 0.01 mol/lof CaCl₂ (pH=7.5) for the determination of the hydroxamic acids up toand including Example 33, or, for the determination of the carboxylicacids from Example 34, 0.1 mol/l of piperazine-N,N′-bis[2-ethanesulfonicacid] pH=6.5.

[0277] The enzyme solution contains 5 μg/ml of one of the enzyme domainsprepared according to Ye et al. The substrate solution contains 1 mmol/lof the fluorogenic substrate(7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2′,4′-dinitrophenyl)-L-2,3-diaminopropionyl-Ala-Arg-NH₂(Bachem, Heidelberg, Germany). TABLE 3 Stromelysine Neutrophilcollagenase Example No. IC 50 [M] IC 50 [M] 1 3*10⁻⁷ 2*10⁻⁸ 2 2*10⁻⁸ 2*10⁻¹⁰ 3 3*10⁻⁸ 2*10⁻⁹ 4 7*10⁻⁷ 1*10⁻⁷ 5 6*10⁻⁶ 3*10⁻⁷ 6 5*10⁻⁷ 3*10⁻⁸8 3*10⁻⁶ 2*10⁻⁷ 9 4*10⁻⁷ 8*10⁻⁷ 10 3*10⁻⁷ 1*10⁻⁷ 11 4*10⁻⁷ 7*10⁻⁸ 124*10⁻⁷ 2*10⁻⁷  13c 2*10⁻⁸ 2*10⁻⁹ 14 3*10⁻⁸ 2*10⁻⁹ 15 1*10⁻⁷ 1*10⁻⁸ 171*10⁻⁷ 2*10⁻⁸ 18 3*10⁻⁸ 3*10⁻⁹ 19 2*10⁻⁶ 3*10⁻⁷ 20 1*10⁻⁸ 1*10⁻⁹ 212*10⁻⁸ 2*10⁻⁹ 22 3*10⁻⁸ 8*10⁻⁹ 23 8*10⁻⁸ 8*10⁻⁹ 24 6*10⁻⁸ 2*10⁻⁸ 254*10⁻⁷ 3*10⁻⁷ 26 6*10⁻⁶ 3*10⁻⁷ 27 3*10⁻⁸ 4*10⁻⁹ 28 2*10⁻⁶ 7*10⁻⁷ 292*10⁻⁸ 4*10⁻⁹ 31 2*10⁻⁸ 3*10⁻⁹ 32 6*10⁻⁸ 7*10⁻⁹ 33 3*10⁻⁷ 7*10⁻⁸ 345*10⁻⁷ 1*10⁻⁸ 35 1*10⁻⁷ 5*10⁻⁹ 36 3*10⁻⁶ 39 1*10⁻⁷ 1*10⁻⁹ 41 (13b)2*10⁻⁷ 9*10⁻⁹ 42 5*10⁻⁷ 2*10⁻⁸ 43 2*10⁻⁶ 2*10⁻⁷ 44 2*10⁻⁷ 3*10⁻⁸ 453*10⁻⁶ 3*10⁻⁷ 46 3*10⁻⁶ 3*10⁻⁷ 50 6*10⁻⁷ 3*10⁻⁸ 51 5*10⁻⁷ 2*10⁻⁸ 521*10⁻⁶ 4*10⁻⁸ 53 5*10⁻⁷ 2*10⁻⁸ 57 2*10⁻⁶ 1*10⁻⁷

[0278] 2. Proteoglycan Degradation Assay

[0279] Principle of the Assay:

[0280] In the proteoglycan degradation assay, the extent of thedegradation of native bovine, aggrecan, the most important proteoglycanof the cartilage, is measured. The released proteoglycan fragments aredetermined using the monoclonal antibody 5-D4 which recognizes thekeratan sulfate side-chains which are located at the carboxy terminal ofthe G2 domain of aggrecan. Thus, the assay detects primarilypathologically important degradations which take place in theinterglobular domain of aggrecan.

[0281] After addition of compounds of the formula I and the enzyme inthe form of the catalytic domain of stromelysine-1, the amount ofhyaluronic acid-bound aggrecan which remains after degradation ismeasured. The more aggrecan is detected, the lower the residual activityof the enzyme. The concentrations of compounds of the formula I at whichthe initial enzyme activity (=100% residual activity) is reduced by half(=50% residual activity) is indicated by the IC50 values in Table 3.

[0282] Description of the Test Protocol:

[0283] Wells of 96 well microtiter plates (Nunc, Maxisorp) eachcontaining 100 μl of hyaluronic acid solution (25 μg/ml of hyaluronicacid (Sigma) in PBS) are incubated at room temperature (RT) for 12 h.The hyaluronic acid solution is removed by suction and the remainingfree protein binding sites of the wells are saturated with in each case100 ml of a 5% strength solution of bovine serum albumin (BSA), 0.05% ofTween20 in PBS at RT for 1 h. The wells are subsequently covered withproteoglycane by incubating the wells with 100 μl each of a solution ofbovine nasal proteoglycane (ICI) (200 μg/ml in 1× PBS, 5 mg/ml of BSA,0.05% of Tween20) at RT for 1 h. The wells are washed twice with 1× PBS,0.1% Tween20 to remove the free proteoglycanes. Subsequently, for theactual assay, 60 ng of purified catalytic domain of Stromelysine-1 (forthe recombinant expression and purification, see Ye et al. (1992)) pluscorresponding concentrations of the inhibitor to be tested in 100 μl ofdegradation buffer (100 mM MES pH 6.0, 100 mM NaCl, 10 mM CaCl₂, 0.05%of Brij) are pipetted into the wells and incubated at RT for 3 h. Thewells are washed twice with 1× PBS, 0.1% of Tween20 and then incubatedwith 100 μl of a solution of the detection antibody (monoclonal antibodyclone 5-D-4 (ICI), immunoreactive with the keratan sulfate side-chainsof the proteoglycane, dilution 1:1000 in 1×PBS, 5 mg/ml BSA, 0.05%Tween20). The wells are washed twice with 1×PBS, 0.1% of Tween20, afterwhich the immune reaction of the bound detection antibodies is carriedout using 100 μl per well of an antibody solution for detection (goatanti Maus IgG, labeled with peroxidase (Dianova), diluted 1:1000 in1×PBS, 5 mg/ml of BSA, 0.05% of Tween20) at RT for 1 h. The wells areagain washed twice (as above), and the color reaction is then initiatedusing 100 μl each of 2 mg/ml of ABTS, activated with H₂O₂. The reactionproducts are measured in an ELISA reader at a wavelength of 405 mm. Theresults are shown in Table 4. TABLE 4 Proteoglycane degradation ExampleNo. IC50 [M] 2 8.5*10⁻⁸ 9 1.6*10⁻⁶  13c 5.1*10⁻⁸ 14 6.7*10⁻⁹ 18 4.1*10⁻⁸20 1.3*10⁻⁷ 21 6.5*10⁻⁸ 29 2.5*10⁻⁸

1. A compound of the formula I

and/or an optionally stereoisomeric form of the compound of the formulaI and/or a physiologically tolerable salt of the compound of the formulaI, where in the case i) R¹ is a) a radical of the formula II

b) a radical of the formula III

c) a radical of the formula IV

where Z is a radical of a heterocycle or a substituted heterocycle suchas 1) pyrrole, 2) thiazole, 3) pyrazole, 4) pyridine, 5) imidazole, 6)pyrrolidine, 7) piperidine, 8) thiophene, 9) oxazole, 10) isoxazole, 11)morpholine or 12) piperazine, d) naphthyl, e) naphthyl, mono- ortrisubstituted by R², or f) a radical of the formula V

where o is the number 1 or 2 and one of the carbon atoms in the ring maybe replaced by —O— or —S—, and Q as part of the structural formula I

1) is the structural moiety VI

2) the structural moiety VII

3) is the structural moiety VIII

4) the structural moiety IX

or 5) is the structural moiety X

where D is NR⁴ or S, R² is 1) phenyl or 2) phenyl which is mono- totrisubstituted by 2.1 hydroxyl, 2.2 —O—R¹⁰, where R¹⁰ 1) is(C₁-C₆)-alkyl, 2) is (C₃-C₆)-cycloalkyl, 3) is benzyl or 4) is phenyl,2.3 —COOH, 2.4 (C₁-C₆)-alkyl, 2.5 (C₃-C₆)-cycloalkyl-O—(C₁-C₄)-alkyl,2.6 halogen, 2.7 —CN, 2.8 —NO₂, 2.9 —CF₃, 2.10 —O—C(O)—R¹⁰ and R¹⁰ is asdefined above, 2.11 —O—C(O)-phenyl, mono- or disubstituted by R³, 2.12—C(O)—O—R¹⁰ and R¹⁰ is as defined above, 2.13 methylenedioxo, 2.14—C(O)—NR¹¹R¹², where R¹¹ and R¹² may be identical or different and eachis 1) a hydrogen atom, 2) (C₁-C₄)-alkyl or 3) benzyl or 4) R¹¹ and R¹²together with the linking nitrogen atom form a pyrrolidine, piperidine,morpholine or piperazine radical, or 2.15 —NR¹³R¹⁴, where R¹³ is ahydrogen atom or (C₁-C₄)-alkyl and R¹⁴ 1) is a hydrogen atom, 2) is(C₁-C₄)-alkyl, 3) is benzyl, 4) is —C(O)—R¹⁰ or 5) is —C(O)—O—R¹⁰ andR¹⁰ is as defined above, R³ and R⁴ are identical or different and eachis 1) a hydrogen atom, 2) (C₁-C₅)-alkyl, 3) (C₁-C₅)-alkoxy, 4) halogen,5) hydroxyl, 6) —O—C(O)—R¹⁰ and R¹⁰ is as defined above, or 7) R³ and R⁴together form the radical —O—CH₂—O—, R⁵ is a) a hydrogen atom, b)(C₁-C₅)-alkyl or c) benzyl, and R⁶, R⁷ and R⁸ are identical or differentand each is a) a hydrogen atom, or b) has, in the case of i), themeaning of R² under items 2.1 to 2.14, and n is zero, 1 or 2, m is zero,1 or 2, the sum of n and m being 1, 2 or 3, or where in the case ii) R¹is 1) phenyl or 2) phenyl, mono- to trisubstituted by R², where R² is asdefined for the case i) under items 2.1 to 2.15, Q is the structuralmoiety X and R⁶, R⁷ and R⁸ are identical or different and each isdefined as above, n is 1 and m is 1, or where in the case iii) R¹, Q,R⁶, R⁷ and R⁸ are identical or different and each has the meaningmentioned for the case ii), m and n are zero, 1 or 2 and where themeanings of n and m are not identical, and X is a) a covalent bond, b)—O—, c) —S—, d) —S(O)—, e) —S(O)₂—, f) —C(O)— or g) —C(OH)—, and Y is a)—O— or b) —S—, and A is HO—NH—C(O)— or HO—C(O)— and B is a) —(CH₂)_(q)—,where q is zero, 1, 2, 3 or 4, or b) is —CH═CH—.
 2. The compound of theformula I as claimed in claim 1 and/or a physiologically tolerable saltof the compound of the formula I and/or an optionally stereoisomericform of the compound of the formula I, where R¹ in the case i) is aradical of the formula II or III and Q is the structural moiety VI, VII,VIII or X, R¹ in, the case ii) is phenyl or phenyl, mono- totrisubstituted by methoxy, and Q is the structural moiety X, or R¹ inthe case iii) is phenyl, Q is the structural moiety X, n is zero and mis 2, and A is HO—NH—C(O)— or HO—C(O)—, B is a covalent bond, X is anoxygen atom or a covalent bond, and R² is phenyl or phenyl substitutedby a) hydroxyl, b) —O—R¹⁰, where R¹⁰ is (C₁-C₃)-alkyl or benzyl, c)(C₁-C₂)-alkyl, d) fluorine or chlorine, e) —CN, f) —CF₃ or g) NR¹³R¹⁴,where R¹³ and R¹⁴ are each (C₁-C₃)-alkyl, R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areidentical or different and each is a) a hydrogen atom, b) methoxy, c)methylenedioxo, d) amino or e) hydroxyl.
 3. The compound of the formulaI as claimed in claim 1 or 2, whereinR-2-(biphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamic acid,R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,R-2-(4-chlorobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,R-2-(4-(4-dimethylaminophenoxy)benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,R-2-(4-dimethylaminobiphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid,R-2-(4-benzoylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-hydroxamicacid,R-2-(4-methoxybenzenesulfonyl)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid,R-2-(4-methoxybenzenesulfonyl)7-nitro-1,2,3,4-tetrahydro-isoquinoline-3-hydroxamicacid,2-(4-methoxybenzenesulfonyl)6,7-propylene-1,2,3,4-tetrahydro-isoquinoline-1-hydroxamicacid,R-5-(4-methoxybenzenesulfonyl)4,5,6,7-tetrahydro-1H-imidazo-(4,5-c)-pyridine-6-hydroxamicacid,R-2-(4-methoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamicacid,R-2-(4-phenoxybenzenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido-(3,4-c)-indole-3-hydroxamicacid are used.
 4. The compound of the formula I as claimed in one ormore of claims 1 to 3, wherein the central carbon atom between amino andhydroxamic acid group is present as R enantiomer.
 5. A process forpreparing the compound of the formula I as claimed in one or more ofclaims 1 to 4, which comprises reacting a) an imino acid of the formulaXI

where the radical Q and n and m are as defined in the formula I with a(C₁-C₄)-alcohol or a benzyl alcohol to give the compound of the formulaXII

where R_(x) is (C₁-C₄)-alkyl or benzyl, or b) reacting a compound of theformula XII prepared according to process a) with the compound of theformula XIII

where R¹ is as defined in formula I and R_(Z) is a chlorine atom,imidazolyl or —OH, in the presence of a base to give a compound of theformula XIV

where Q, R¹, n and m are as defined in formula I and R_(x) is as definedin formula XII, or c) reacting a compound of the formula XII preparedaccording to process a) with a base and subsequently with a compound ofthe formula XIII to give a compound of the formula XIV, or d) reacting acompound of the formula XI with a compound of the formula XIII to give acompound of the formula XV

where Q, R¹, n and m are as defined in formula I, or e) reacting acompound of the formula XIV to give a compound of the formula XV, or f)reacting a compound of the formula XIV prepared according to process b)or c) with the hydroxylamine of the formula XVI H₂N—OR_(y)   (XVI) whereR_(y) is a hydrogen atom or a protective group for oxygen, to give thecompound of the formula I and, if appropriate, removing the protectivegroup for oxygen, or g) reacting a compound of the formula XV preparedaccording to process d) or e) with the hydroxylamine of the formula XVIto give the compound of the formula I, or h) separating into the pureenantiomers a compound of the formula I prepared according to process for g) which, owing to its chemical structure, exists in enantiomericforms, by forming salts with enantiomerically pure acids or bases, bychromatography using chiral stationary phases or derivatization by meansof chiral enantio-merically pure compounds such as amino acids,separation of the resulting diastereomers, and removal of the chiralauxiliary, or i) isolating the compound of the formula I preparedaccording to processes f), g) or h) either in free form or, if acidic orbasic groups are present, converting it, if appropriate, intophysiologically tolerable salts.
 6. A pharmaceutical, comprising anefficacious amount of at least one compound as claimed in one or more ofclaims 1 to 4 or as obtained as claimed in claim 5 and/or aphysiologically tolerable salt of the compound of the formula I and/or astereoisomeric form of the compound of the formula I, together withphysiologically acceptable auxiliaries and excipients, optionallyfurther additives and/or other active compounds.
 7. The use of at leastone compound of the formula I as claimed in one or more of claims 1 to 4for preparing pharmaceuticals for the prophylaxis and therapy ofdisorders in the course of which an increased activity ofmatrix-degrading metalloproteinases is involved.
 8. The use as claimedin claim 7 for the treatment of disorders of the connective tissue suchas collagenoses, periodontal disorders, wound healing disorders orchronic disorders of the locomotory apparatus such as inflammatorily,immunologically or metabolically related acute and chronic arthritides,arthropathies, myalgias and disorders of the bone metabolism ordegenerative joint disorders such as osteoarthrosis, spondylosis,chondrolysis after joint trauma or relatively long joint immobilizationafter meniscus or patella injuries or ligament tears, or for thetreatment of ulceration, artherosclerosis and stenoses, or inhibition ofthe release of tumor necrosis factor, or for the treatment ofinflammations, carcinomataceous disorders, formation of tumormetastases, cachexia, anorexia and septic shock.
 9. A process for theproduction of a pharmaceutical as claimed in claim 6, which comprisesbringing into a suitable administration form at least one compound ofthe formula I as claimed in one or more of claims 1 to 4 and/or at leastone physiologically tolerable salt of the compound of the formula Iand/or an optionally stereoisomeric form of the compound of the formulaI, using physiologically acceptable auxiliaries and excipients and, ifappropriate, further additives and/or other active compounds.